Beta-chloroethylamines



Patented June 22, 1954 2,681,933 fi-GHLOROETHYLAMINES William B. Wheatley, Syracuse, N. Y., assignor to Bristol Laboratories Inc., Syracuse, N. Y., a corporation of New York No Drawing. Application November 25, 1949, Serial No. 129,515

3 Claims. (Cl. 260570) This invention relates to a new class of organic compounds of therapeutic value and methods for the preparation thereof. More particularly the invention relates to compounds of the series of substituted N-beta-(o-benzylphenoxy) ether-N- beta-halogen amines and acid addition salts thereof.

The free base of the new compounds may be represented by the following general formula CH2 R2 R1 R and R1 represent hydrogen, halogen, lower alkyl and alkoxy groups. R2 is hydrogen, alkyl one to ten carbon atoms straight and branched, cycloalkyl and aralkyl. R3 is hydrogen, alkyl, alkenyl and aryl. X is halogen.

The acid addition salts of these compounds are also included within the present invention. Some examples of the acid addition salts of the base with inorganic and organic acids which may be prepared by the methods hereinafter described are the hydrochlorides, hydrobromide, hydroiodide, sulfate, phosphate, maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, phthalate, and the like.

The compounds of the present invention have been found to possess valuable therapeutic properties particularly as sympatholytic and antihistaminic agents. As an example N-beta-(obenzylphenoxy) ethyl-N-beta-chloroethyl-ethylamine is five times as active as Dibenamine in blocking epinephrine in cats and more active than Bena-dryl histamine in guinea pigs.

The compounds of the present invention may be prepared from the corresponding beta-hydroxyethylamines by refluxing with excess thionyl chloride in chloroform or ether solution.

Refluxing the appropriate beta-benzylphenoxyethyl halide with a twofold molar amount of betaalkyl-aminoethanol in an inert solvent gave the expected aminoalcohol in good yield. Because the chlorides are more easily prepared they are to be preferred over the bromides.

The required beta-benzylphenoxyethyl halides may be prepared by condensing the sodium phenoxide with ethylene dibromide or betachloro-ethyl-p-toluenesulfonate.

The following examples will serveto illustrate the invention without limiting it thereto. All temperatures are centigrade unless otherwise in dicated.

Example 1 Beta-(o-benzylphenowy) ethyl chloride- T0 a stirred suspension of 36 grams (1.5 moles) of sodium hydride in 300 ml. of toluene, under a nitrogen atmosphere, is added dropwise a solution of 276 grams (1.5 moles) of o-benzylphenol in 750 ml. of toluene. After the addition is completed, the mixture is refluxed until all the sodium hydride disappears. To this clear solution, stirred and maintained at reflux by external beating, is added dropwise 368 grams (1.57 moles) of betachloroethyl-p-toluenesulfonate. A white precipitate appears at once. After 16 hours refluxing, 45 ml. of 56% potassium hydroxide solution is added and the mixture subjected to steam distillation until no more toluene appears in the distillate. The two-phase residue is poured into a beaker and stirred vigorously while cooling. The oily layer solidifies, and is collected by filtration. Recrystallization of the crude solid from 'cyclohexane gives 330 grams (89% yield) of beta- (o-benzylphenoxy) ethyl chloride, M. P. 62455". An analytically pure sample melts at 65.0-66.0.

Analysis-Calculated for C15H15OC1 Calculated Found Example 2 Calculated Found Example 3 Beta-(p-chloroo benzylphenomy) ethyl chloride.-This compound is prepared in the manner described in Example 1, by using p-chloro-obenzylphenol in place of o-benzylphenol. It melts at 46.5-48.5".

3 4 Analysis.-Calculated for C15H14OC1z ether stripped. Distillation of the residual oil gives 255 grams (88% yield) of N-beta-(o-benzyl- Calculated Found phenoxy ethyl N-beta-hydroxyethyl ethylamine,

B. P. 178 at 1 mm., n 1.5363. C 4 64.4 Analysis.Ca1culated for C19H25O2N H 5 0 5.1

Calculated Found Example 4 Beta [o-(p-chlorobenzyl)phenomylethyl chlog ride.-This compound is prepared in the manner described in Example 1, by using l-(p-chlorobenzyDphenol in place of o-benzylphenol. 1t Example 8 does not solidify; the residue "from steam 'dis- N -beta (o-baneylphenoxy) ethyl N-beta-hytillation is therefore extracted with ether and dram/ethyl :methylamine-This compound may the product obtained by distillation in vacuo. It be prepared in the manner described in Example boils at 43 at 1 mm- "l'by using beta-methylaminoethanol in place of AnaZysis.Calculated for 0151-1140012 beta-ethylaminoethanol. It boils at 202-203 at 2.4.mm.; n 1.5628. Calculated Found Analys'ia-Calculated for CmHzsOzN C 64.1 61.3 Calculated Found H 5.0 5.3

Example 5 Beta [o- (p-chlorobenzyl) phenom/l ethyl chlo- Mia-This compound'is prepared in the manner described in Example 4 by using o-(p-fluorobenzyDphenol. It'boils from 144 to 147 at 2 mm.

.Analysis.-Calculated for CisHMOClF Calculated Found Cum Example '6 Beta- (obeneylpheno:ry) ethyl iodide.A solu tion of 61.1 grams (0.25 mole) of beta-(o-benzylphenoxy) ethyl chloride and 37.8 grams (0.25 mole) of sodium iodide in 250 ml. of acetone is refluxed for 16 hours; cooled and filtered. The filtrate is concentrated to two-thirds its original volume, then poured into 500 m1. of water and ml. of saturated-sodium bisulfite solution. The solid product is collected by filtration and recrystallized from cyclohexane, giving 74 grams (87% yield of beta-(o-benzylphenoxy)ethy1 iodide,

M. F. 88-95. Further recrystallization raises the melting point to 9598.

Analysis:-Calculated for C15H15OI Calculated Found Example 7 dried with anhydrous sodium sulfate and the Example 9 Calculated Found Example 10 N-beta-(o-benzylphenoxy)ethyl N beta-hydroxyethyl-n-butylamine.+This compound may may be prepared in'the manner described in Example 7, by using "beta-n-butylaminoethanol in place of beta-ethylaminoethanol. It boils at 199- '205 a't'1.5 mm.; nb l.5460.

Analysis.-Calculated for C21H29O2N Calculated Found Example 11 Calculated .Found Example 12 .N-beta-(o-benzylphenoxy) ethyl N beta-hydroatyethyl isobutylamine.-'This compound may be prepared in the manner described in Example 7 by using beta-isobutylaminoethanol in place of beta-ethylaminoetha-nol. It boils at 184-188" at 1 mm; 17 -1.5438.

Analysis.-Calculated for C21H29O2N 6 aminoethanol. It boils at 224-225 at 1 mm; n -1.5644.

Analysis.-Calculated for C19H25O3N Calculated Found 5 Calculated Found 0 77. 0 77. 2 o 72. 4 72. 3 H 8.9 9.0 H 8.0 8.3

Example 13 19 Example 18 N -beta(o-benzylphenoa:y) ethyl N beta-hy N -beta-(o-benzylphenomy) ethyl N beta hyd'roazyethyl Z-ethylhe:cylamtne.This compound droacypropyl tsopropylamtna-This compound may be prepared in the manner described in EX- may be prepared in the manner described in Example'lby using beta-(2-ethylhexylaminoethanol ample '7, by using 1-isopropylamino-2-propanol in place of beta-ethylaminoethanol. It boils at in place of beta-ethylaminoethanol. It boils at 224-225 at 2 111111.; n -l.5310. 167-17? at 1 mm.; n -LMOO.

Analysis.-Calculated for C25H37O2N Analysts.-Calcu1ated for (7211 12902131 Calculated Found lCalculated Found 0 78.3 78. 2 o 77.0 77 0 H 9. 7 9.4 H 8.9 8 9 Example 14 Example 19 N-beta (0 benzylphenoxy) ethyl-N-hydromy- N beta a o-benzylphenomy) ethyl N-beta-vmylethyl bellzylamme-*Thls coinpoupd may beta-hydrozvyethyl isop-ropylcmine.This comprepared m the manner .descrmed Example 7 pound may be prepared in the manner described by using beta-benzylammoethanol in place of in Example 7' by using a vinyl beta isopropyl betaeithylgmmoebhanol' It bolls at at aminoethanol in place of beta-ethylaminoethanol. 1 "1 It boils at 187-190 at 1 mm., n 1. 5466.

Anclyszs.-Calculated for C24H27O2N Analysis calculated for C22H29O2N Calculated Calculated Found Example 15 v Example 20 N -beta-(o-lzenzylyhenomy) ethyl N beta-hy- Nmetmcwbenwmhenomy)ethyl droxyethyl cycZohemylamme-Thxs compound yl beta ethyl isopropylamine.--This may be prepared 1n the manner deicmbed m compound is prepared as described in Example ample '7 by using beta-cyclohexylammoethanol in from beta (o benzylphenoxy) ethyl chloride place of beta-ethylaminoethanol. It boils at 223- r and a pheny1 beta isopropylaminoethanoL It and melts at 520-530 after crystallizes out when the reaction mixture is excl'ysta'l*lz atlon from petroleum Ethel" tracted with dilute hydrochloric acid and can AnalysZs-Ca1cu1ated for C23H31O2N be isolated by filtration. Recrystallization from isopropyl alcohol-water gives a colorless solid, Calculated Found M. P. 1'73.5.79.5.

Analysis.--Ca-lculated for C26H31O2N-HC1 o 78.1 73.1 H 8-8 '0 Calculated Found Example 16 g 78.3 72.3 7.0 ".6 N -beta- (o be'nzylphenoxy) ether beta-hydroxyethyl 2-phenyltsopropylamlne.-This compound is prepared from beta-(o-benzylphenoxy) ethyl Example 21 iodide and beta-(2-phenylisopropyl amine)etha N beta [o p chlorobeneyl)phenoasylethyl n01 according to the procedure described in Ex- N-beta-hydroznyethyl isop1-opylamtne.This comample 7. It boils at 220-221" at 1 mm.; 77 pound may be prepared as described in Example 1.5734. '7 from beta-[0-(p-chlorobenzyl)phenoxylethyl Analysis.-Calculated for CzsHsrOzN chloride and beta-isopropylaminoethanol. It boils at 188-19(l at 1 mm., n 1.'5556. Calculated Found Calculated Found 0 80.1 79.1 H 0 8 C 69,1 9. 2 H 7.5 7.7 Example 17 N-beta-(o-benzylphenomy)ethyl bis(beta hy- Emample 22 drozcyethyl) amine-This compound may be pre N beta (p chloro o benzylphenoscy) ethyl pared in the manner described in Example 7 N-beta-hydromyethylisoproyyZamine.This comby using diethanolamine in place of beta-ethylpound may be prepared as described in Example ace-1,933

'7 from beta-(p chloro-o benzylphenoxy) ethyl chloride and beta-isopropylaminoethanol. Itboils at 180-184" at 1 mm, M. P.'56.5-57.5.

Analysis.-Calculated for C20H26O2NC1 recrystallized from isopropyl alcohol-petroleum ether, giving 32.2 grams of N-beta-(o-benzylphenoxy) ethyl N-beta-chloroethyl isopropylamine hydrochloride, M. P. 138.0-1390".

Analysis-Calculated for CzoHzsONCl-HCI Calculated Found I Calculated Found 0 69.1 69.1 H 7.5 7.4 V

o 65.2 65.2 H 7.4 7.5 Example 23 N beta [o (p fluorobeneyl)phenoxylethyl Example 27 N -beta-hydroatyethyl isopropyZamine-This compound may be prepared as described in Example I benzylphenom N f 7 from beta [0 (p fiuorobenzyl)phenoxy] methyl n-bulylamzne hydrochlorzde.This comethyl chloride and beta-isopropylaminoethanol. pound may be prepared from Nbeta(o'benzyl' It boils at 1914960 at 1 mm phenoxy) ethyl N beta hydroxyethyl n butyl- Anazysis cavlculamfl for CZGH2GO2NF amine according to the method described in Example 26. It melts at 110.0-111.0 after recrystallizationfrom ethyl acetate-ether. l Calculated AndZysis.Calculated for C21HzaONC1-HC1 C 72.5 72.5 "H u T 9 7- 4 I Calculated Found c 66 0 6' 9 Example 24 IiIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 7Z7 3:6 N -betap-benzylphenoacy) ethyZ-beta-hydroxyethyl isopropylamine.This compound may be prepared as described in Example 7 from beta- Example 28 D" D 0 y) ethyl chloride and beta-iSO- N-beta-(o-benzylphen-oxy)ethyl N-beta-chlopropylaminoethanol. It bolls at 206-213 at 1 methyl sec. butylamine hydrochloride.A solum1n., n .5 i88. tion of 9.5 grams of thionyl chloride in 100 m1. AnaZysis.Calcu1ated for C2O 27 2 of ether is added dropwise to an ice-cold, stirred solution of 1737 grams (0.054 mole) of N-beta-(o- Calculated Found benzylphenoxwethyl N beta hydroxyethyl sec. butylamine in 250 ml. ofether. After the addition 76,3 has been completed, the reaction mixture is refiuxed for three hours. The solid is recrystallized from isopropyl alcohol-ether to give 12.9 Example 2 5 grams of N-beta- (o-benzylphenoxy)ethyl N-betachloroeth l' e'cabut larn'ne h r 11 Vi. N beta (o benzylphenoazy) ethyl N betai- 107 5 y 1 yd 0c 1 01 l P chloroel'hyl melhylamine hydrochloride-To an A'nal ale 1 C I ice-cold stirred solution of 42.7 grams (0.15 yszs' C u ated fol zlIIzaONCl E01 mole) of N beta (o benzylphenoxy ethyl N- beta-hydroxyethyl methylamine in 158 ml. of Calculated Found chloroform is added dropwise 26.5 ml. of thionyl chloride. After the ECIditiOIl is complete, the g:I: I mixture is allowed to come to room temperature r and finally refluxed for 20 minutes. The 501- vent and excess thionyl chloride are evaporated Example 29 under reduced ressure. The residue is dissolved in of warm benzene a nd the benzene N'beta."(o'bemyzphenoxy)ethyl then evaporated under reduced pressure. This methyl zsobutyle'ine i fi c 'f treatment with benzene is repeated and the resipound be plep,areq f1 Om due purified further by recrystallization from isophepoky) N new Y Y J lsoputyl' propyl alcohoL There is obtained in this amine according to the method described in Exner 354 grams of N beta (o benzylphenoxy) ample 28. It melts at 10l.0-103.0 after recrystalethyl I -beta-chloroethyl methylamine hydrohzatlon j ethyl acetate' chloride; 1V1- P 0 118 0o 60 Analyszs.-Calcu1ated fOI' C2lH28ONClHC1 AnaZysis.-Calculated for CmHzzONCl-HCI Calculated! Found Calculated Found 0 66.0 66.0 5 H 7.7 7.9 o 63.5 63.6 H 6.8 6.8

Example 30 Example 26 I N-beta-(o-beneylphenomy)ethyl N-beta-chlo- N-beta-(o-benzylphenoxy)ethyl N-beta-hy- 7 methyl ethylamine hydrochloride.This comdroxyethyl isopropylamine in 100 m1. of ether is pound may be prepared from ll-beta-(o-benzyladded dropwise to an ice-cold stirred solution of phenoxy)ethyl N-beta-hydroxyethyl ethylamine 15 m1. of thionyl chloride in 100 m1. of ether. Folaccording to the procedure described in Example lowing the addition, the mixture is refluxed for 28. It melts at 161.0-163.5 after recrystallization one hour. The solid is collected by'filtration and 75 .from isopropyl alcohol-ethyl acetate.

9 Analysis.--Calculated for C19Ha4ONC1-HC1 Calculated Found Example 31 N -beta- (o-benzylphenoxy) ethyl N -beta-chloroethyl Z-ethylheccylamzne hydrochloride.-This compound may be prepared from N-beta-(obenzylphenoxy) ethyl N-beta-hydroxyethyl 2-ethylhexylamine according to the method described in Example 25. It melts at 82.5-84.5" after recrystallization from methyl isobutyl ketone-petroleum ether.

Analysis.-Calculated for CzsHasONCl-HCI Calculated Found Example 32 N -beta- (o-benzylphenoxy) ethyl N -beta-chloroethyl beneylamine hydrochloride.-This compound may be prepared from N-beta-(o-benzylphenoxy) ethyl N-beta-hydroxyethyl benzylamine according to the procedure described in Example 28. It melts at 151.0-l53.5 after recrystallization from isopropyl alcohol.

Analysls.-Calculated for CzlHzaoNCl-HCl Calculated Found Example 33 N -beta- (o-benzylphenoxy) ethyl N -beta-chlomethyl cycloheaylamine hydrochloride-This compound may be prepared from N-beta-(obenzyl phenoxy) ethyl N-beta-hydroxyethyl cyclohexylamine according to the method described in Example 25. It melts at l08.5110.0, after recrystallization from methyl isobutyl ketone.

Analysis.-Calculated for C23H30ONC1'HC1 Calculated Found Example 34 N-beta- (o-beneylphenoxy) ethyl N-beta-chloroethyl Z-phenyllsopropylamtne hydrochloride- This compound may be prepared from N-beta-(obenzylphenoxy) ethyl N beta hydroxyethyl 2- phenylisopropylamine according to the method described in Example 25. It melts at l53.0-.55.0 after recrystallization from methyl isobutyl ketone.

Analysis.-Calculated for CzeHsoONCl-HCI Calculated Found Example 35 N -beta- (o-benzylphenoxy) ethyl bis (beta-chloro'ethybamlne hydrochloride-This compound may be prepared from N-beta-(o-benzylphe- 1G noxy ethyl bis(beta-hydroxyethyl) amine according to the method described in Example 28; one more equivalent of thionyl chloride is used because of the presence of an additional hydroxyl group. It melts at 155.0-15811 after recrystallization from isopropyl alcohol.

Analysis.Calculated for C19H23ONC12'HC1 Calculated Found Example 36 N -beta- (o-beneylphenoxy) ethyl N -beta-chloropropyl isopropylamine hydrochloride-This compound may be prepared from N-beta-(o-benzylphenoxy)ethyl N-beta-hydroxypropyl isopropylamine according to the'method described in Example 26. It melts at 11'7.0-l18.5 after recrystallization from methyl isobutyl ketone.

Analysis.-Calcula-ted for C21H28ONC1'HC1 Calculated Found Emample 37 Calculated Found Example 38 N -=beta- (o-beneylphenomy) ethyl N -beta-phenyl beta chloroethyl isopropylamme hydrochloride-This compound may be prepared from N-beta- (o-benzylphenoxy) ethyl N -beta-phenylbeta-hydroxyethyl isopropylamine according to the method described in Example 28. It melts at 124.5-127.0 after recrystallization from methyl isobutyl ketone ether.

Analysis.-Calculated for CasHsoONCl-HCI Calculated Found Example 39 N beta-[o (p ehlorobenzyl)phenoazylethyl N beta chloroethyl lsopropylamlne hydrochloride-This compound may be prepared from N-beta [o (p chlorobenzybphenoxylethyl N- beta-hydroxyethyl isopropylamine according to the procedure described in Example 25. It melts at l31.0-l33.5 after recrystallization from ethyl acetate.

Analysis.Calculated for CzoHzsONCla Calculated Found Ewample 40 N-beta- (p-chloro o benzylphenomy) ethyl N- beta-chloroethyl isopropylamine hydrochloride- This compound may be prepared from N-beta- (pchloro-o-benzylphenoxy) ethyl N-beta-hydroxyethyl isopropylamine according to the method described in Example 26. It melts at 146.0-147.0 after recrystallization from isopropyl alcohol;

Analysis.-Calculated for; C20H25ONC12 HCl Calculated Found Example 41 Calculated Found Example 42 N -beta- (p-benzylphenoxy) ethyl beta chloroethyl isopropylamine hydrochZoride.-This compound may be prepared from N-beta-(p-benzylphenoxy) ethyl beta-hydroxyethyl isopropylamine according to the method described in Example 28;

It melts at 106.0109.5. after. recrystallization from methyl isobutyl ketone.

Analysis-Calculated for C20H26ONC1'HC1 Calculated Found I claim:

1. A new class of compounds consisting of the free bases and the acid addition salts thereof, said free bases being members selected from the group consisting of bases having the formulae CH1 CH(CH3)2 CH(CH3):

2. A compound of the formula 3. A compound of the formula References Cited in the file of this patent UNITED STATES PATENTS Name Date Alquist et a1 Aug. 19, 1941 OTHER REFERENCES Rieveschl' et al., Amer. Chem. Soc, Abstracts of Papers, 112th Meeting, September 1947, p. 17k.

Achenbach et al., Fed. Proc., vol. 7, p. 258 (March 1948).

and

Number 

1. A NEW CLASS OF COMPOUND CONSISTING OF THE FREE BASES AND THE ACID ADDITION SALTS THEREOF, SAID FREE BASES BEING MEMBERS SELECTED FROM THE GROUP CONSISTING OF BASES HAVING THE FORMULAE 